The results summarized below were obtained in collaborative studies: Recent studies suggest that the M1 mAChR represents a potential target for the treatment of neuropsychiatric disorders including schizophrenia. Since patients with schizophrenia show impairments in top-down processing involving conflict between sensory-driven and goal-oriented processes, we used a touchscreen-based cognition task that mimics these deficits. We found that M1 mAChR knockout (M1 KO) mice showed a slower rate of learning in the touchscreen-based cognition task, as compared to wild-type littermates. Moreover, the M1-selective positive allosteric modulator BQCA enhanced the rate of learning in the touchscreen test in wild-type but not in M1 KO mice. Thus, it is likely that the performance deficits displayed by the M1 KO mice in touchscreen cognitive assessments involve impairments in 'top-down processing'. Our data support the concept that agents that are able to selectively facilitate signaling through central M1 receptors may prove useful to treat the cognitive symptoms associated with schizophrenia. (Gould RW, et al. Role for the M1 muscarinic acetylcholine receptor in top-down cognitive processing using a touchscreen visual discrimination task in mice. ACS Chem Neurosci, 2015 Aug 5. Epub ahead of print PMID: 26176846) Many studies have shown that mAChRs modulate dopaminergic transmission in the striatum which plays a key role in locomotor and reward processes. Considerable controversy exists regarding the mechanisms through which mAChRs modulate striatal dopamine (DA) release. In a collaborative study, we therefore investigated mAChR-mediated DA release from three types of midbrain neurons that all project to the striatum: DA, DA/glutamate, and glutamate neurons. Using different mAChR KO mice, we found that M5 receptors potentiate DA and glutamate release only from DA and DA/glutamate projections from the midbrain, while M2/M4 receptors depress striatal DA release induced by activation of nicotinic receptors. These findings support the view that M5 receptors on DA neuron terminals enhance DA release, whereas M2/M4 autoreceptors on cholinergic terminals inhibit ACh release which subsequently triggers nicotinic receptor-dependent DA release. This study clarifies the cellular mechanisms through which distinct mAChR subtypes modulate DA and glutamate transmission in the striatum. (Shin JH, Adrover MF, Wess J, Alvarez VA. Proc Natl Acad Sci USA 112, 8124-9, 2015) In a collaborative study, we recently demonstrated that signalling through M3 mAChRs plays an important role in adaptive immunity to both Nippostrongylus brasiliensis and Salmonella enterica serovar Typhimurium. Specifically, we demonstrated that M3 receptor KO mice were impaired in their ability to resolve infection with either pathogen. The mutant mice showed several immunological deficits, including impaired CD4 T cell activation and reduced cytokine production. Taken together, our findings support the view that M3 receptor signaling is essential for optimal Th1 and Th2 adaptive immunity to infection. (Darby M, et al.. The M3 muscarinic receptor is required for optimal adaptive immunity to helminth and bacterial infection. PLoS Pathog 11, e1004636, 2015) Studies with M3 receptor KO mice suggest that M3 receptors regulate neutrophilic inflammation in response to cigarette smoke (CS). M3 receptors are present on almost all cell types in the pulmonary system. In a collaborative study, we investigated the relative contribution of M3 receptors on structural cells vs. inflammatory cells to CS-induced inflammation using bone marrow chimeric mice. Our findings support the concept that M3 receptors on structural cells play a pro-inflammatory role in CS-induced neutrophilic inflammation, whereas the M3 receptors on inflammatory cells do not. Our data suggest that these pro-inflammatory effects mediated by M3 receptor signaling are likely to involve altered adhesion and transmigration of neutrophils via fibrinogen-&#945; and CD177. (Kistemaker LE, et al. Muscarinic M3 receptors on structural cells regulate cigarette smoke-induced neutrophilic airway inflammation in mice. Am J Physiol Lung Cell Mol Physiol 308, L96-103, 2015) Several studies suggest that activation of central M4 mAChRs may be able to ameliorate the severity of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. In a collaborative study, we investigated whether VU0467154, a novel positive allosteric modulator (PAM) of M4 receptor function, could reduce the behavioral, cognitive, and neurochemical impairments induced by administration of MK-801, a noncompetitive NMDAR antagonist. In wild-type mice, VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task. These VU0467154 effects were not observed in M4 receptor KO mice. Interestingly, VU0467154 also promoted the acquisition of contextual and cue-mediated fear conditioning in wild-type mice. These novel findings suggest that M4 receptor PAMs may prove beneficial for the treatment of the complex affective and cognitive impairments associated with schizophrenia and other neuropsychiatric disorders. (Bubser M, et al. Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents. ACS Chem Neurosci 5, 920-42, 2014)